Our research group at the University of Pittsburgh has recently developed a promising, non-invasive, in vivo PET tracer for imaging amyloid deposition in living humans. Known as Pittsburgh Compound-B (PiB), it has shown much promise in documenting pre-symptomatic amyloid deposition in living subjects destined to develop Alzheimer's disease (AD). PiB also provides a means to determine the natural history of amyloid deposition. While there has been increasing use of PiB to assess amyloid deposition in cognitively normal individuals, the fact remains that despite identifiable risk factors that increase the likelihood of acquiring AD (e.g., age, family history, ApoE4), we cannot identify with certainty those who will develop AD. This makes the study of pre-clinical amyloid deposition difficult in the general population. Conversely, individuals with Down syndrome (DS) are at high risk for developing AD due to the presence of an extra copy of chromosome 21, which codes for the Af3 precursor protein (APP) gene. Postmortem studies have documented the presence of AD pathology in 60 to 90% of adults with DS (with greater pathology increasing with age)(Sylvester, 1984;Wisniewski et aI., 1985). Additionally, symptoms of AD occur in over 40% for DS individuals between 50 and 59 years of age (Hyman, 1992;Schupf et aI., 1998). Thus, the study of adults with DS provides a valuable opportunity to follow the natural history of amyloid deposition and compare it to clinical symptomatology - knowing that approximately half of the group will eventually develop clinical AD and an even greater fraction will develop amyloid deposits. Toward that end, the current multi-center proposal (University of Pittsburgh and Massachusetts General Hospital) will document amyloid deposition in 64 nondemented/ functionally stable adults with DS over a two-year period. We will study three age cohorts: 30-39 yrs, 40-49 yrs and .2:.50 yrs. Subjects will also be assessed for the presence ofthe apolipoprotein-E4 (ApoE4) allele to determine its possible association with accelerated deposition brain amyloid. While we will not complete a natural history study of amyloid deposition in DS during the current project period, this effort will lay the foundation by gathering a valuable cohort of PiB+, non-demented DS subjects that we can follow beyond this grant period with future funding.